N-triiodobenzyl-carbamic acid derivatives

ABSTRACT

Water-soluble salts of pharmaceutically acceptable bases with N(2,4,6-triiodo-3-acylamino-5-carboxy-benzyl)-carbamic acid esters of the formula   ARE RELATIVELY NON-TOXIC, QUICKLY EXCRETED X-ray contrast agents suitable for intravenous administration. The carboxylic acids of the formula are monoesters of alcohols R1OH having up to four carbon atoms which are alkanols, mono- and dihydroxyalkanols, or alkoxyalkanols, when n is 1, and diesters of alcohols HO-R1-R1OH having up to 10 carbon atoms which are alkanediols or ethyleneglycol ethers when n is 2. R2 has up to three carbon atoms and is alkyl, hydroxyalkyl, or alkoxyalkyl.

United States Patent 1 Felder et al.

i 1 N-TRlIODOBENZYL-CARBAMIC ACID DERIVATIVES [75] Inventors: Ernst Felder; Davide Pitre, both of Milan, Italy [73] Assignee: Bracco lndustria Chimica, Societa per Azioni, Milan, Italy 22 Filed: June 24,1974

2| Appl.No.:482,665

Primary Examiner-Robert Gerstl Assistant Examz'nerL. A. Thaxton Almrney, Agent or FirmHans Berman; Kurt Kelman Oct. 7, 1975 [57] ABSTRACT Water-soluble salts of pharmaceutically acceptable bases with N-(2,4.6-triiodo-3-acylamino-5-carboxybenzyl)-carbamic acid esters of the formula are relatively non'toxic, quickly excreted X-ray contrast agents suitable for intravenous administration. The carboxylic acids of the formula are monoesters of alcohols R 0H having up to four carbon atoms which are alkanols, monoand dihydroxyalkanols, 0r alkoxyalkanols, when n is l, and diesters of alcohols HO-R,R OH having up to 10 carbon atoms which are alkanediols or ethyleneglycol ethers when n is 2. R has up to three carbon atoms and is alkyl, hydroxyalkyl, or alkoxyalkyl.

9 Claims, N0 Drawings N-TRIlODOBENZYL-CARBAMIC ACID DERIVATIVES This invention relates to X-ray contrast agents, and particularly to radiopaque derivatives of triiodobenzoic acid capable of intravenous administration in aqueous solution, to the synthesis of such contrast agents, and to the use of compositions containing the same.

Such derivatives include the known X-ray contrast agents most effective and least toxic when used for vasography, urography, and cholecystography. Yet, the known compounds are not always tolerated well enough, nor do they provide images of adequate contrast under difficult conditions, and the search for improvement continues.

It has now been found that derivatives of 2,4,6-triiodo-S-acylbenzoic acid carrying a side chain R -OCO-NH--CH in position 3 offer significant advantages over the present state of this art. The injectable contrast agents of this invention are watersoluble salts of pharmaceutically acceptable bases with N-( 2.4,6-triiodo- 3-acylamino-5-carboxy-benzyl carbamic acid monoesters and diesters of the formula C OOH wherein n is l or 2, R has up to four carbon atoms and is alkyl, hydroxyalkyl, or alkoxyalkyl when n is l, and R is one half of divalent alkylene or of oxaalkylene having 2 to carbon atoms and up to four oxygen atoms when n is 2, while R has up to three carbon atoms and is alkyl, hydroxyalkyl, or alkoxyalkyl.

lnjectable X-rays contrast agents must withstand thermal sterilization in aqueous solution, and it was surprising to find that the amide bond in the carbamate side chains in the contrast agents of this invention resists hydrolysis more strongly than a simultaneously present ester linkage or some ether linkages, as will become evident hereinafter. Aqueous solutions of the contrast agents may be safely subjected to sterilization at high temperature.

Many esters of the invention which are free carboxylic acids are insoluble or only sparingly soluble in water. They are useful primarily as intermediates in the preparation of the salts. The physiologically tolerated alkali and alkaline earth metal salts and many amine salts are sufficiently soluble in water so that injectable solutions containing 45 to 500 mg iodine per milliliter can readily be prepared. The preferred metal salts are the sodium salts. Lithium salts may be employed under some conditions, and the magnesium and calcium salts may be used jointly with the alkali metal or amine salts in smaller amounts. The amines which may constitute the base moiety in the salts are those commonly used in galenic pharmacy in salts with physiologically active acids and include N-methylglucamine, N- methylxylamine l-methylamino-l-desoxy-[Dl-xylite), l-methylamino-2, 3-propanediol diethanolamine, monoethanolamine, tris-( hydroxymethyl aminomethane, and many others. The pharmaceutically acceptable bases are in themselves irrelevant to the action of the compounds as X-ray contrast agents for visualizing body cavities into which the compounds are introduced.

The salts of monoesters in which R is alklyl, monohydroxyalkyl, dihydroxyalkyl, or alkoxyalkyl are eminently suitable for vasography and urography. Some are better tolerated then the best contrast agents now available for the same purpose. They are preferentially excreted by the kidneys at high concentration so as to provide good opacity for urography without remaining in the body for an extended period, whereby side effects are minimized.

The diesters of the invention are predominantly excreted by the liver and concentrate in the bile. Only a small portion is quickly excreted by the kidney. The remainder produces dense and well differentiated X-ray images of the gall bladder and also good images of the bile ducts. The diesters are better tolerated than the commonly used, intravenously administered contrast agents for cholecystography. Their toxicity is as low as that of the best-tolerated contrast agents for urography and vasography available heretofore. Some of the diesters of the invention may be employed for vasography, and their solutions have lower osmotic pressures than those of the monoesters of the invention at equal iodine concentration.

Table l lists relevant properties of N- methylglucamine salts of nine monoesters of the invention together with those of well-known X-ray contrast agents preferred heretofore by many radiologists for intravenous urography.

The carboxylic acids in the tested salts and the Examples in which the preparation of the compounds of the invention is described hereinbelow are identified in Table l by numbers as follows:

1: N-( 2,4,6-triiodo-3-acetylamino-5-carboxybenzyl)-carbamic acid methyl ester (Example I N-( 2,4,6-triiodo-3-propionylamino-5-carboxybenzyl)-carbamic acid methyl ester {Example 2) 3: N-( 2,4,6-triiodo-3-hydroxyacetylamino-5- carboxy-benzyl)-carbamic acid methyl ester (Example 4) N-( 2,4,6-triiodo-3-hydroxyacetylamino-5- carboxy-bcnzyl)-carbamic acid ethyl ester (Example 8) 5:

N-( 2,4,6-triiodo-3-methoxyacetylamino5- carboxy-benzyl)-carbamic acid ethyl ester (Example 9) N-(2,4,6-triiodo-3-acetylamino-5-carboxy-benzyl)-carbamic acid B-hydroxyethyl ester (Example I l 7: N-( 2,4,6-triiodo- 3-hydroxyacetylamino-5- carboxy-benzyl)-carbamic acid B-hydroxyethyl ester (Example 13) 8: N-( 2,4,6-triiodo-3-acetylamino-5-carboxy-benzyl )-carbamic acid B-methoxyethyl ester (Example 17) 9: N-( 2,4,6-triiodo-3-methoxyacetylamino-5- carboxy-benzyl)-carbamic acid B-methoxyethyl ester (Example l8) l0: 3,5-Bis-(acetylamino)-2,4,6-triiodobenzoic acid AMI DOTRIZOATE) l l: 3-Acetylaminomethyl-5-acetylamino-2,4,6-

triiodobenzoic acid (lODAMlDE) l2: 5Acetylamino-2,4,6-trii0d0-N- methylisophthalamic acid (IOTALAMIC ACID) The toxicities listed were determined as LD in male white mice after intravenous injection of aqueous solutions and are expressed in mg iodine per kg body weight. Excretion with the bile and with urine were determined after intravenous injection in anesthetized rabbits carrying catheters in their urcters and bile ducts. Iodine in the secreted liquids was determined by an automatic analyzer, and the percentage of injected contrast agent excreted within three hours after the injection was caluclated from the analytical data.

Identical standard methods were employed in all tests whose results appear in the several appended Tables so that these results are directly comparable.

As is evident from Table I, the contrast agents of the invention, Nos. 1 to 9, compare favorably with the three known contrast agents Nos. to 12, in their toxicities, in their specific excretion by the kidney, and in the rapidity with which they are discharged from the body. Compounds l, 3, 4, and 8 and distinctly superior to the well-tolerated known compounds.

Table II shows toxicity and excretion data analogous to those of Table l for seven diesters of the invention and for three known contrast agents for cholecystography. The tested compounds were N-methylglucamine salts of carboxylic acids identified by capital letters as follows:

A; Di-N-(2,4,o-triiodo-3-acetylamino-S-carboxybenzyl)-carbamic acid ethyleneglycol ester (Example B: Di-N-( 2,4,b-triiodo-3-acetylamino-5-carboxybenzyU-carbamic acid l,3-propanediol ester (Example Di-N-( 2,4,6-triiodo-B-acetylamino-S-carboxyhenzyl )-carhamic acid 1 ,4-butanediol ester (Example 2l D: Di-N-( 2,4,6-triiodo-3-acetylamino-5-carboxyhenzyI)-carbamic acid l,6-hexanediol ester (Example 22) Dl-N-( 2,4,o-triiodo-3-acetylarnino-5-carboxybenzylrcarbamic acid diethyleneglycol ester (Example 23) F: Di-N-( 2,4,6-triiodo-3-acetylamino-S-carboxy-bcn- 2yl)-carbamic acid triethyleneglycol ester (Example 24 G: Di-N-( 2,4,6-triiodo-3-hydroxyacetylamino5- carboxy-benzyl)-carbamic acid ethyleneglycol ester (Example 25) H: Ad ipinoyl-bis-( 3-carboxy-2,4,6-triiodoanilide) (ADIPIODONE, US. Pat. No. 2,776,241)

I: Diglycoloyl-bis-(3-carboxy-2,4,o-triiodo-anilide) (IOGLACAMIC ACID, U.S. PAT. No. 2,776,24l)

K: 4,7, l0, 1 3-Tetraoxahexadecanel l6-dioyl-bis-( 3- carboxy-2.4,6-triiodanilide) (IODOXAMIC ACID, US. Pat. No. 3,654,272).

Table III shows the results of cholecystographic and cholangiographic examination of dogs I and cats (2) 0.5, l. 2, 4, 6, and 8 and hours after intravenous injection of N-methylglucamine salts of the carboxylic acids A K at a dosage of I00 mg acid per kg body weight. The choleeystographic data are expressed as Hoppe Index values (.I. O. Hoppe, J.Am. pharm. Assn., Sci. Ed., 48 I959] 368-379). On Hoppe's scale, contrast of an X-ray image is evaluated as follows:

0 none 1 weak 2 adequate 3 good 4 excellent The results of cholangiography simultaneous with the cholecystography are averages arrived at in a manner analogous to HOppe's method and based on the following scale:

0 bile ducts not visualized l cystic duct visible 2 common bile duct visible 3 hepatic duct visible 4 intraphepatic bile duct visible As is evident from Table II, the lethal dose LD for the compounds of the invention is 2 to 5 times greater than that of compound H, the contrast agent most commonly used heretofore. The toxicity of compounds A, B, E, F, and G is substantially lower than that of the relatively well tolerated known contrast agents I and K. The dicsters of the invention are more selectively excreted by the liver than the known materials. Even compound B, least effective among the compounds of the invention in this respect, is well above the average of the three known contrast agents.

All monoesters of the invention are excreted almost completely within three hours after the injection into the veins of standard laboratory test animals, thereby avoiding side effects whigh might be caused by extended retention of the contrast media in the body after urography or vasography.

The compounds of the invention are prepared from 3-aminomethyl-5-amino-2,4,6-triiodobenzoic acid or precursors thereof having the formula COOH wherein A is amino or nitro, X X X are iodine, chlorine, or hydrogen, by reaction steps whose sequence may be changed as desired. A triiodobenzoic acid derivative of formula (I) is reacted with a carboxylic acid ester of the formula R --OCO-Y (ll), wherein Y is halogen (preferably chlorine, but also bromine or iodine) or aryloxy, and R,, has up to four carbon atoms and is alkyl, hydroxyalkyl, dihydroxyalkyl, alkyloxyalkyl; hydroxyalkyl or dihydroxyalkyl having at least one masked hydroxyl group, one half of divalent alkylene or oxaalkylene having up to ten carbons and up to four oxygen atoms, or with phosgene and an alcohol R OH. Hydroxyl groups may be masked by esterification, by formation of a readily split ether, or by an acetal or ketal. The resulting compound OOH may require hydrogenation to convert A to amino if it was nitro, to convert X X X, to hydrogen if they where chlorine initially, and it may require conversion of X;,, X X. to iodine if they were hydrogen before. The resulting carbamic acid ester is of the formula (III) in which A is amine and X X X,, are iodine. It is then reacted with an acid of the formula R COOH (IV) in the presence of a dehydrating agent, or with an anhydride or chloride of the last-mentioned acid in which R, is lower alkyl, hydroxyalkyl masked by ester or ether formation, or alkoxyalkyl.

The compound (ll) may thus be an ester of a carbonic acid halide (chloroformate) or a mixed carbonic acid ester having one aliphatic alcohol moiety and an aryloxy group such as phenoxy, tolyloxy or nitrophenoxy.

The preferred starting material is 3-aminomethyl-5- amino-2-4-6-triiodobenzoic acid which is preferably reacted with an ester of chloroformic acid to an N- (2,4,6-triiodo-3amino-5-carboxy-benzyl )-carbamic acid ester or urethane, whereupon the 3-amino group is acylated so that the desired N-( 2,4,6-triiodo-3- acylamino-S-carboxy-benzyl)-carbamic acid may be recovered. Masking groups employed to protect hydroxyl groups in the acyl radical or in the alcohol moiety of the urethane may be split off during recovery, as by gentle heating in an alkaline medium.

The diesters of dihydric alcohols according to the invention are obtained in an analogous manner from 3- aminomethyl-5-amino-2,4,6-triiodobenzoic acid by reaction with chloroformates of the formula Cl-COOZ-OCOCl wherein Z has 2 to carbon atoms and is alkylene or oxaalkylene having up to four oxygen atoms, and subsequent acylation of the reaction product.

Instead of 3-aminomethyl-5-amino-2,4,6- triiodobenzoic acid, precursors may be employed as starting materials if they contain an aminomethyl group attached to a benzene nucleus in meta-position to a carboxyl group. Such a precursor may be reacted with a chloroformate or analogous reactant to form an N- benzyl carbamic acid derivative which may then be fur ther processed to the desired compound.

Preferred precursors include 3-amino-5- aminomethyl-benzoic acid, 3-nitro-5-aminomethylbenzoic acid, and the mono or dihalogen derivatives thereof having halogen in positions 2, 4, and/or 6 of the benzene ring (Helv. Chim. Acta 48 [1964] 259-274). The product of reaction of the precursor with the chloroformate or its equivalent may then require hydrogenation to convert the nitro group to amino, and to replace halogen by hydrogen. The hydrogen formed or originally present in positions 2, 4, 6 of the benzene ring is then replaced by iodine in a conventional manner, as by reaction with iodine chloride or an alkali metal iododichloride.

The reaction between 3-amino-5-aminomethyl-2,4,6- triiodobenzoic acid or its precursors and the chloroformate is carried out preferably in an aqueous medium or IJNNNNNNN in a water-miscible organic solvent at a temperature between approximately 0C and approximately 40C.

To avoid undesired side reactions involving hydroxyl groups in the reactants, such hydroxyl groups are preferably masked by esterification or formation of readily split ethers. If two adjacent hydroxyl groups are present in the same reactant, they may be protected reversibly by masking with an acetal or ketal group.

Suitable masking acid moieties for ester formation include the aliphatic acyloxy groups having up to four carbon atoms, and halogen (chlorine, bromine, iodine), and ethers may be formed with oxygen-linked benzyl, diphenylmethyl, triphenylmethyl (trityl), or trimethysilyl groups. Acetals may be derived from formaldehyde, acetaldehyde, or benzaldehyde, while acetone may furnish a ketal group.

The masking groups are readily removed during recovery of the desired product after acylation of the 3- amino group by gentle heating in an alkaline aqueous medium, by acid hydrolysis, or by transesteriflcation. Removal of the masking groups normally does not involve a reaction step not otherwise required during recovery.

Compounds of the invention which are alkoxyalkylesters of a carbamic acid derivative, or which include an alkoxyacylamino group directly attached to the benzene nucleus, may be formed by reaction of an alcoholate with the corresponding haloalkylester or the corresponding haloacylamino group.

The compositions of the invention which may make a body cavity opaque to X-rays when administered, preferably by intravenous injection in a sufficient concentration, may consist essentially of a physiologically tolerated liquid carrier, and a compound of the formula COOH wherein R and R may be combined, by way of example, if n is l, in the following manner:

If n is 2, R, may be one half of the radicals listed below in combination with the groups represented by R and indicated on the same line:

The following Examples are further illustrative of the compounds of the invention, of their preparation, and of their use.

EXAMPLE l N-( 2,4,6-Triiodo-3-acetylamino-S-carboxy-benzyl carbamic acid methyl ester (Compound No. l)

I g 3-Aminomethyl-5-amino-2,4,6-triiodobenzoic acid (0.l84 mole) (Helv. Chim.Aeta 48 [l965] 259) was suspended in 750 ml water, and l84 ml l-N aqueous sodium hydroxide was added to produce a clear solution. To this solution, there were added simultaneously and drop by drop a solution of 18.5 ml methyl chloroformate (0.24 mole) in 50 ml acetone and l-N aqueous sodium hydroxide I84 ml) over a period of somewhat more than 1 hour at such a rate as to keep the pH of the agitated solution between I and l I.

The reaction mixture was then filtered to remove a small amount of insoluble material, and the filtrate was stirred into dilute hydrochloric acid. Crude N-(2,4,6- triiodo-3 -amino-5-carboxy-benzyl )-carbamic acid methyl ester precipitated and was filtered off with suction, washed with water, and dissolved in a small amount of water with sodium bicarbonate. The sodium salt of the acid was crystallized from the solution by the addition of concentrated sodium chloride solution. It was filtered off and dissolved in water, and the purified acid was precipitated from the aqueous solution with dilute hydrochloric acid and recovered in an amount of 89.5 g (SL371 yield). It melted at l2l-l22C and was identified by its equivalent weight of 60! (calculated: 60l .9) and elementary analysis:

An R, value of 0.50 was found in a thin layer chromatogram using a butanol/acetic acid/water system 3:l:2. The same solvent mixture was employed in all reported TLC tests unless stated otherwise.

A mixture of IS g N-(2,4,o-triiodo-3-amino-5- carboxyl-benzyl)-carbamic acid methyl ester (0.03 mole), 40 ml glacial acetic acid, l0 ml acetic anhydridc, and 0.1 ml sulfuric acid was heated on a steam bath for four hours, and then allowed to stand at ambient temperature overnight. The precipitate formed from the initial solution was filtered off with suction, washed with water, and purified by dissolution in sodium hydroxide solution and reprecipitation with hydrochloric acid.

Compound No. l was obtained in an amount of l6.9 g (87% yield). melted at l75l80C, and gave an R, value of 0.48. It was identified by its equivalent weight of 642 (calculated: 643.94) and by elementary analysis:

EXAMPLE 2 N-( 2 4,6-Triiodo-3-propionylamino-S-carboxy-benzyl)-carbamic acid methyl ester (Compound No. 2)

22.5 g N-(2,4,6-Triiodo-3-amino-5-carboxy-benzyl)- carbamic acid methyl ester (0.0374 mole) prepared according to Example 1, 45 ml propionic anhydride, and 3-4 drops concentrated sulfuric acid were stirred on a steam bath for about 4 hours. The excess of propionic anhydride was evaporated in a vacuum, and the residue was extracted with water and thereafter dissolved in dilute hydroxide solution. The solution was kept at 50C and pH l0-l0.5 for about 30 minutes. Compound No. 2 was precipitated from the solution with dilute hydrochloric acid and purified by way of the ammonium salt.

Pure Compound No. 2 was obtained in an amount of 22 g yield), melted at l66l67C, and gave an R, value of 0.5. It was identified by elementary analysis:

The free carboxylic acid is insoluble in water, benzene, chloroform, and ethyl acetate, readily soluble in methanol and ethanol. At 20C, l00 ml water dissolves 50 g of the sodium salt and at least I00 g of the N- methyl glucamine salt.

EXAMPLE 3 N-( 2 ,4,6-Triiodo-3-butyrylamino-5 -carboxy-benzyl carbamic acid methyl ester Calculated for C H I N O Found:

The free carboxylic acid is insoluble in water, benzene, and chloroform, but dissolves readily in methanol. The sodium and N-methylglucamine salts are water-soluble.

EXAMPLE 4 N-( 2,4,6-Triiodo-3-hydroxyacetylamino-S-carboxybenzyl) carbamie acid methyl ester (Compound No. 3)

22.5 g N-(2,4,6-triiodo-3-amino-5-carboxy-benzyl)- carbamic acid methyl ester (0.037 mole) was dissolved in 90 ml dimethylacetamide, and l0.9 g acetylglycolic acid chloride (0.08 mole) was added dropwise at 0C within about 20 minutes with stirring which was continued for l5 hours at room temperature. The reaction mixture was then stirred into 250 ml water. The precipitate formed thereby was suspended in ISO ml water, heated to 50C, adjusted to pH 9.5 with l-N sodium hydroxide additions as needed until the desired 3- hydroxyaeetylamino side chain was formed. The reaction mixture was decolorized with charcoal and added dropwise to dilute hydrochloric acid, whereby Compound No. 3 was precipitated in an amount of 21.7 g (88.3% yield).

It had a melting point of 196l 99C and an R; value of 0.405. It was identified by its equivalent weight of 661 (calculated: 659.94) and by elementary analysis:

Calculated for C zt fl fl Found:

EXAMPLE 5 N-( 2,4,6-Triiodo-3-methoxyacetylamino-S-carboxybenzyl)-carbamic acid methyl ester 24 g N-(2,4,6-Triiodo-3-amino-5-carboxy-benzyl)- carbamic acid methyl ester (0.04 mole) was dissolved in 60 ml dimethylformamide, and about ml of the solvent was distilled off to remove any water present. ln a separate flask, 9 g methoxyacetic acid (0.1 mole) was dissolved in 50 m1 dimethylformamide, and l 1.9 g thionyl chloride (0.1 mole) was added dropwise at 23C over minutes. The two solutions were combined minutes later, and the mixture was stirred at room temperature, while the gradual disappearance of the starting ester was monitored by TLC. After 15 hours, the reaction mixture was poured into 400 ml water, whereby 24.8 g of the desired product was precipitated (92% yield). It was purified by conversion to the cyclohexylammonium salt. It melted at 245C and had an R, value of 0.46. It was identified by elementary analysis:

Calculated for C H ,,l,-,N O,,: Found:

EXAMPLE 6 N-( 2,4,6-Triiodo-3-acetylamino-S-carboxy-benzyl carbamic acid ethyl ester A solution of 218 g 3-aminomethyl-5-amino-2,4,6- triiodobenzoic acid (0.4 mole) in 1500 ml water and 400 ml l-N sodium hydroxide solution was mixed at room temperature with a solution of 43.2 g ethyl chloroformate (0.4 mole) in 150 ml acetone which was added dropwise together with 400 ml l-N sodium hydroxide solution to keep the pH at 10-1 1. Thereafter, stirring was continued for about 1 hour, and the solution was adjusted to pH 7 and extracted with ethyl acetate and chloroform. Organic solvent was removed from the aqueous liquid in a vacuum, and the liquid was then poured into 1 100 m] dilute hydrochloric acid. The crude N-( 2,4,6-triiodo-3-amino 5 carboxy-benzyl carbamic acid ethyl ester so obtained was dissolved in 200 ml water and 40 ml l0-N sodium hydroxide. The sodium salt was salted out with NaCl as described in Example I and recovered in an amount of 201 g (83% yield). lt decomposed at 225C and gave an R, value of 0.60.

61.8l'll 61.70

Calculated for: C H a z i Found:

The ester was converted to the desired 3-acetylamino derivative as described in Example 1, and the latter was recovered in a yield of 73%. 1t melted at l50-155C, and had an R, value of 0.54. It was identified by its equivalent weight of 655 (calculated: 657.96) and by elementary analysis:

It is only sparingly soluble in water and chloroform, readily soluble in methanol and ethanol. Water at 20C dissolves more than its own weight of the sodium and N-methylglucamine salts.

EXAMPLE 7 Calculated for C, ,H l N Q-a Found:

It is only sparingly soluble in water and chloroform, but readily dissolves in methanol.

The 3-butyrylamino derivative was obtained in a yield of 73%, melted at l46-l47C. and had an R, value of 0.66.

Calculated for C,,-.H, l;,N,O F ound:

The acid is sparingly soluble in water and chloroform, readily soluble in methanol, and absorbs one mole of crystal water from moist air.

EXAMPLE 8 N-( 2,4,6-Triiodo-3-hydroxyacetylamino-S-carboxybenzyl)-carbamic acid ethyl ester (Compound No. 4)

24.8 g N-( 2,4,6-Triiodo-3-amino-5-carboxy-benzy1)- carbamic acid ethyl ester was dissolved in 50 ml dimethylacetamide, and 13.6 g acetylglycolic acid chloride (0.1 mole) was added. The mixture was stirred 18 hours at room temperature and then poured into 400 m1 ice water with stirring. The crude acetyl derivative of Compound No. 4 was precipitated, filtered off with suction, washed with a little water, and dissolved in dilute sodium hydroxide solution. The solution was heated to C and kept at pH 10 by addition of dilute sodium hydroxide solution until saponification was achieved as indicated by stabilization of the pH without further need of sodium hydroxide additions. Compound No. 4 was then precipitated by means of 18% hydrochloric acid and recovered in an amount of 25 g Calculated for C H J N -U I 2.

Found:

The acid absorbs l mole crystal water from moist air. dissolves in boiling water. in methanol and in ethanol, but is only slightly soluble in cold water and chloroform. The sodium and N-methylglucamine salts readily dissolve in water.

EXAMPLE 9 N-( 2,4,6-Triiodo-3-methoxyacetylamino-S-carboxybenzyl)-carbamic acid ethyl ester (Compound No. S)

9 g Methoxyacetic acid (0.1 mole) was dissolved in 50 ml dimethylformamidc, and l L9 g thionyl chloride (0.l mole) was added dropwise with stirring and ice cooling over l minutes. Stirring thereafter was continued for about I hour at room temperature, whereupon 24.8 g N-(2.4,6 triiodo-B-amino-S-carboxy-benzyl)- carbamic acid ethyl ester (0.04 mole) was added. The reaction mixture was stirred vigorously for about 12 hours and then poured with stirring into 300 ml water. The precipitate formed thereby was filtered off with suction, washed with cold water, and purified by dissolution in dilute sodium hydroxide solution and precipitation with hydrochloric acid. Compound No. 5 was reobtained in an amount of l9.2 g (85% yield). It melted at 162 l 63C.

alculatcd for C H N O Found:

A solution of 0.02 mole of the compound so obtained in 150 ml water and ml l-N sodium hydroxide solution was hydrogenated at room temperature in the presence of 0.5 g 1071 palladium catalyst on active carbon. After the amount of hydrogen (1350 ml) necessary for hydrogenation of the No -group had been absorbed, the catalyst was filtered off, and I000 ml water was added to the filtrate together with enough dilute hydrochloric acid to make the pH 2. 70 ml 1-N Potas sium iododichloride (KlClsolution then was added with stirring which was continued for 12 hours.

The precipitated, crude N-(2,4,6-triiodo-3-amino-5- carboxy-benzyl)-carbamic acid isopropyl ester was filtered off with suction and dissolved in ml water and the necessary minimum amount of 20% sodium hydroxide solution. The sodium salt was then precipitated by means of saturated sodium chloride solution, filtered off at 0C washed with a little saturated sodium chloride solution, and dissolved in 200 ml water. The solution was decolorized with active carbon, and added dropwise to dilute hydrochloric acid to precipitate the purified ester in an amount of 8.7 g (69% yield). It melted at 2092 l0C Calculated for H...I,N. .O.;

Found Eq.m.629.99

The end product then was obtained by acetylation as 227228C. and gave an R, value of 0.4. in Example I in a yield of 62%. It melted at Calculated for C H l N o t 24.4471 C; 55.34% I; Eq.wt.688.0

Foundl 24.26 55.54 685 The acid is oorly soluble in water and chloroform, but 4 238240C. When recrystallized from ethanol. it

dissolves in boiling methanol or ethanol. The sodium and N-mcthylglucamine salts dissolve freely in cold water.

changed its crystal form and melted at I95C. An R, value of 0. l 8 was established on silica gel with a butyl acetate/glacial acetic acid/water solvent 5:l:l.

Found:

EXAMPLE l0 N-( 2.4,o-Triiodo-3-acetylamino-S-carboxy-benzyl carbamic acid isopropyl ester l7.l g 3-Aminomethyl-5-nitrobenzoic acid (0.08 mole) was dissolved in l00 ml water, 50 ml ethanol. and ml 2-N sodium hydroxide, and the solution was cooled with ice and kept at pH 10-] l by dropwise addition of 40 ml 2-N sodium hydroxide solution while a solution of IO gisopropyl chloroformate (0.08 mole) in 40 ml acetone was added drop by drop. The reaction mixture was evaporated to a vacuum to I ml and acidified with hydrochloric acid. The precipitated. crude N-( 3-nitro-5-carboxy-benzyl)-carbamic acid isopropyl ester was recrystallized from ethanol, and was The free carboxylic acid is insoluble in water, but soluble in boiling ethanol. Water at 20C dissolves an equal weight of the sodium or N-methylglucamine salt.

EXAMPLE 1 l N-( 2,4,6-Triiodo-3-acetylamino-5-carboxy-benzyl carbamic acid B-hydroxyethyl ester (Compound No. 6)

2L5 g Benzyloxyethyl chloroformate (0.] mole) and l00 ml l-N sodium hydroxide solution were added dropwise and simultaneously with stirring to a solution of 54.3 g 3-aminomethyl-5-amino-2,4.o-triiodobenzoic acid (0.] mole) in ml water and 100 ml l-N sodium hydroxide at l0 to l5C at a rate to maintain a pH of 10 to l l. The reaction mixture then was adjusted to pH 7, extracted with chloroform and ethyl acetate.

stripped of residual solvent in a vacuum, and stirred into dilute hydrochloric acid. The precipitate was purified by dissolution in dilute sodium hydroxide solution at a pH not exceeding 7, removal of undissolved matedroxide solution while a pH of l-l l was maintained. Thirty minutes later, enough hydrochloric acid was added to adjust the pH to 7. The acetone was evaporated in a vacuum, and the aqueous solution was filrial by filtering, and precipitation with dilute hydrotered and added dropwise to very dilute hydrochloric chloric acid. acid. The precipitate formed was washed with water N-(2.4, rii0 0- -umin0-5-car xyenzy and dissolved in aqueous sodium bicarbonate solution. earbamic acid B-benzyloxyethyl ester was recovered in The resulting solution was filtered and mixed with 100 an amount of 54.75 g (76% yield) and melted at l4lC g sodium chloride to precipitate the sodium salt of N- (decomp) and gave an R, value of 0.85. (2.4,6-triiodo-3-amino-S-carboxy-benzyl)-carbamic Calculated for C|-H|fl3N2Q 1 29.9471 C; 52.73% I, eq.wt.722.06 Found: 29.44 53. l5 720 Acetylation under the conditions of Example 1 acid B-chloroethyl ester. The salt was filtered off with yielded the B-bcnzyloxyethyl ester analogous to Comsuction, washed with saturated sodium chloride solupound No. 6 which melted at l l51 17C. tion, dissolved in water, and decomposed with hydro- 80.6 g N-(2,4,6-triodo-3aminomcthyl-S-carboxychloric acid. The precipitated free carboxylic acid benzyl)-carbamic acid B-henzyloxyethyl ester (0.l2 20 weighed I37 g (84.5% yield). intCred at 13 C. and mole), prepared as described above, was mixed with d C mP at l70 ml glacial acetic acid and ml acetic anhydride, the mixture was heated to 95C, and 1.7 ml concentrated sulfuric acid was added with stirring. The result- CnHwClbNwOfi Equim'cm wcigh c 7 Found: 654 mg clear solution was kept about 3 hours at 95 C and then evaporated to dryness in a vacuum. The residue "W when ground ethyl etherh was An R, value of0.61 was established with chloroform/msolved in dilute sodium hydroxide solution and exh ku-n ]k j l i l acetic id 105:2 tracted with chloroform and ethyl acetate. The purified 21 5 g flcm h l esmr prepared as d ib d i aqueous solution then was stripped of residual organic h preceding paragraph ((1033 was digg h/ d i solvent in a vacuum and stirred into dilute hydrochloric 45 l water containing 85 g potassium hydroxidg 11Cidwhereby gof a mixture of (0.1 mole). The solution was stored overnight at 0C ucetylumino-Sclll'boxybenzyl)Cafbflmic B- yand then added dropwise to dilute hydrochloric acid to droxyelhyl ester 11nd of the Corresponding precipitate to B-hydroxyethyl ester formed by saponifi- B- mxy hy ester 1 W115 formed- 35 cation of the chloroethyl derivative. The crude product The mixture w i lv in 0 l Water m 90 ml was largely dissolved in dilute sodium hydroxide, and l-N sodium hyroxide solution, and the solution so ohh l ti w adjusted to pH 6. A small amount of tained was kept at 50C and further supplied with dilute undis olved 3 aminomethyl-5-amino-2,4,6- sodium hydroxide solution until the pH remained Contriiodobenzoic acid was removed by filtration, and the stunt. It was then filtered and acidified carefully. The filtrate was acidified to precipitate the purified carinitial amorphous precipitate was discarded. Upon adbamic acid ester. dition of much more acid. Compound No. 6 crystall8 g Purified ester was dissolved in 20 ml methanol, lized. It was recovered in several successive runs in the solution was deeolorized with active carbon, filyields of 56% to 65%. sintered at l55C, and deeomtered, and mixed with a solution of 3 ml cyclohexylposed at l 74C. R, 0.36. amine in 20 ml ethanol. The resulting precipitate of the Calculated for C H I N O 23.17% C; 56.49% I; eq.wt.673.97 Found: 23.00 56.] l 679 Compound No. 6 is soluble in boiling water, readily cyclohexylammonium salt was filtered off with suction, soluble in methanol and ethanol, poorly soluble in chlowashed with methanol, suspended in water, and dis roform. The sodium and N-methylglucamine salts dissolved by added 2-N sodium hydroxide solution. The solve easily in water at 20C. cyclohexylamine so liberated was removed by extrac- The excess of acetic anhydride in the acetylation retion with ethyl acetate, and the pure B-hydroxyethyl action caused replacement of the B-benzyloxy-grou ester was precipitated from the aqueous phase with by an acetyloxy-group which ultimately was hydroacid, and recovered in an amount of 14.3 g (68% lyzed. yield). It sintered at 125C, decomposed at 174C, gave EX 2 an R, value of 0.40 with chloroform/methylethylk- 1 etone/glacial acetic acid [0:522, and had an equivalent *2igggjzigggzg g 'ifi z weight of 625 (631.93 calculated for C H I N O y Y Y Y e5 12.6 g (0.02 Mole) of the last-prepared ester was sus- 35.8 g B-Chloroethyl chloroformate (0.25 mole) dis pended in 25 ml propionic anhydride, a few drops consolved in 200 ml acetone and 250 ml l-N sodium hycentratcd sulfuric acid were added, and the mixture droxide solution were added to a solution of I28 g 3- aminomethyl-5-amino-2,4,6-triiodobenzoic acid (0.25 mole) in 1000 ml water and 250 ml l-N sodium hywas held on a steam bath for 2 hours and thereafter left to stand overnight. A crystalline precipitate then was filtered off with suction and dissolved in dilute sodium 54.3 g 3-Aminomethyl-5-amino-2,4.6-triiodobenzoic acid (0.1 mole) was dissolved in 100 ml water and 100 ml l-N sodium hydroxide solution. l50 Ml ofa 16% solution of l-benzyloxy-Z-butyl chloroformate in acetone and 100 ml l-N sodium hydroxide solution were added dropwise to the first-mentioned solution at to [5C with stirring at such a rate as to keep the pH of the mixture between l0 and 11.

The mixture was further processed as in Example I l to produce N-(2,4,6-triiodo-3-amino-5-carboxy-benzyl)-carbamic acid a-ethyl-B-benzyloxyethyl ester in a yield of 65.5%. The ester sintered at about 60C, melted at 81C, and gave an R, value of 0.70.

Found:

eq.wt.750.l I

The free acid dissolves only sparingly in water and chloroform, but readily in methanol and hot ethanol. More than equal weights of the sodium or N- methylglucamine salts dissolve in water at C.

EXAMPLE l3 N-( 2 ,4,6-Triiodo-3-hydroxyacetylamino-S-earboxybenzyl)carbamic acid B-hydroxyethyl ester (Compound No. 7)

25.3 g (0.04 Mole) N-(2,4,6-triiodo-3-amino-5- Calculated for C H I N O Found:

carboxy-benzyU-carbamic acid B-hydroxyethyl ester, prepared as in Example 12, was reacted in 50 ml dimethylacetamide at room temperature with 21.8 g (0.16 mole) acetoxyacetyl chloride, and the reaction mixture was worked up as described in Example 8. The product initially obtained was a tacky mass which was heated to about 80 to 95C before being separated from the aqueous liquor, whereby it crystallized. The crude crystalline material g) was dissolved in 75 ml anhydrous ethanol, and the solution was mixed with 4 ml morpholine. causing immediate precipitation of the morpholine salt of Compound No. 7. After 2 hours, the precipitate was filtered off with suction, dissolved in water, and decomposed by adding the solution drop by drop to dilute hydrochloric acid at 50C. The suspension so obtained was further heated to 80and filtered with suction. 23 g Compound No. 7 was obtained (83.5% yield). It decomposed at l86C. An R, value of 0.48 was determined by TLC on silica gel with methylethylketone/glacial acetic acid/water/ethanol 20:3:3z3.

The free earboxylic acid is soluble in boiling water, and it dissolves readily in methanol and ethanol. The sodium and N-methylglucamine salts dissolve freely in cold water.

EXAMPLE I 5 N-( 2 ,4.6-Triiodo-3-acctylamino-5 -carboxy-ben zyl carbamic acid l,3-dihydroxyisopropyl ester 83.2 g l,3-Formalglycerol (5-hydroxy-l,3-dioxane) (0.8 mole) was added dropwise and with agitation to a solution of 99 g (1 mole) phosgene in 1000 ml ethyl ether at 0 i l0C. The temperature was then permitted to rise slowly to 20C, and the mixture was ultimately refluxed for 2 hours. The solvent was evaporated at ambient pressure, and the residue was distilled in a vacuum to yield 95 g l,3-formalglyceryl chloroformate boiling at l06l08C at l4 mm Hg (71.5% yield).

A solution of 33.3 g (0.2 mole) l,3-formalglyceryl chloroformate in 100 ml acetone and 200 ml l-N so- Calculated for C H i N 0 Found:

Compound No. 7 dissolves little in water and chloroform, readily dissolves in ethanol, and even more readily in methanol. The sodium and N- methylglucamine salts are very soluble in water at 20C.

EXAMPLE l4 N-( 2,4,6-Triiodo-3-acetylamino-5-carboxy-benzyl carbamic acid a-ethyl-B-hydroxyethyl ester Calculated for C,,,H,,,|,,N.o,,; Found:

23.7 g (0.035 mole) N-(2,4,6-triiodo-3-amino-5- carboxy-benzyl)-carbamic acid 1,3-formalglycery1 ester was acetylated as described in preceding Examples in 70 ml glacial acid with 70 ml acetic anhydride and 0.1 ml sulfuric acid. The reaction mixture was evaporated to dryness in a vacuum, and the residue was suspended in water. The suspension was adjusted to pH l 1, and this pH was maintained for 15 minutes by adding sodium hydroxide solution as needed. The mixture thereafter was kept at 70 to 80C for about 25 minutes, whereby an almost clear solution was formed. Residual solid matter was removed by filtering, and the filtrate was acidified to pH 2. A small amount of precipitate formed and was removed by again filtering. The filtrate so obtained was evaporated to dryness in a vacuum.

The residue was repeatedly extracted with methanol, the combined extracts were decolorized with active carbon and evaporated to dryness. The residue weighing 24 g melted at 94 to 100C. It was dissolved in absolute ethanol, and 2.4 ml cyclohexylamine was added propylidene-glyceryl chloroformate in 100 ml acetone and 100 ml l-N sodium hydroxide solution were added dropwise at 10 to 15C at a rate to maintain a pH value of 10-1 1. The crude product formed was recovered in the manner described in Example 6 and dissolved in dilute sodium hydroxide solution which was adjusted to pH 1 1 and added dropwise to dilute hydrochloric acid 1 hour later to precipitate 47.25 g of the 2,3-dihydroxypropyl carbamate (71.5% yield). The acetone formed was lost during subsequent drying. The ester sintered at 125C and decomposed at 187C.

Calculated for C H,;,1=,N O,,: Found:

36.4 g N-(2,4,6-Triiodo-3-amino-5-carboxy-benzyl carbamic acid 2,3-dihydroxypropyl ester (0.055 mole) in 260 ml glacial acetic acid and 28 g acetic anhydride (0.275 mole) were heated with stirring to 95C, 10 drops concentrated sulfuric acid was added, and heating was continued for about 2 hours whereupon the mixture was evaporated to dryness in a vacuum. The residue crystallized when triturated with water. The crystals were filtered off with suction and dissolved in dilute sodium hydroxide solution. The solution was adjusted to pH 1 1, heated to 50C. and kept at pH 1 1 by further addition of sodium hydroxide until the acetoxy groups were saponificd. Upon acidification, the 2,3-dihydroxypropyl ester of N-(2,4,6-triiodo-3- acetylamino-S-carboxy-benzyl)-carbamic acid gradually crystallized. lt was recrystallized from water and weighed 23.5 g (617: yield), sintered at 172C, decomposed at 185C, and gave an R; value of 0.29.

Calculated for C H, ,l,-,N O,:

Found:

to the solution to precipitate the cyclohexylammonium salt of N-(2,4,6-triiodo-3-acetylamino-5-carboxy-benzyl)-carbamic acid 1,3-dihydroxyisopropyl ester which was recovered by filtration with suction, washed with a little ethanol, and dissolved in water. The solution was passed over a column of 200 m1 Amberlite 1R-l20, a cation exchange resin in the H form, and the desired ester in the free carboxylic acid form was recovered from the eluate by vacuum evaporation to dryness in an amount of 14.5 g (59%). 1t melted at 106C and gave an R, value of 0.40 in a thin layer chromatogram with a solvent system of ethyl acetate/ethanol/7c ammonium hydroxide solution 1 1:7:6. The acid is soluble in water, methanol, and ethanol.

EXAMPLE 17 N-( 2,4,6-Triiodo-3-acetylamino-S-carboxy-benzyl carbamic acid B-methoxyethyl ester (Compound No. 8

Solutions of 163.2 g 3-Aminomethyl-5-amino-2,4,6- triiodobenzoic acid (0.3 mole) in 1000 ml water and 300 m1 l-N sodium hydroxide solution, of 41 g B-me- Calculated for C,..H,,1,,N. ,O;: 23.89% C; 54.08% 1, eq.wt.704.00 Found: 23.64 53.81 714 EXAMPLE l6 thoxyethyl chloroformate (0.3 mole) In 100 ml ace- N-( 2,4,6-Triiodo-3-acetylamino-5-carboxy-benzyl carbamic acid 2,3-dihydroxypropyl ester 54.3 g 3-Aminomethyl-5-amino-2,4,6-triiodober1zoic tone, and of sodium hydroxide in water (300 m1 l-N) were combined at pH l0l l as in the preceding Examples, and the carbarnic acid ester formed thereby was recovered and purified in the manner more fully described above. It weighed 181 g (94% yield), melted at 182C, and gave an R, value of 0.63.

The compound is sparingly soluble in water and chloroform, readily soluble in ethanol. The sodium and N- methylglucamine salts freely dissolve in cold water.

EXAMPLE l9 39 g N (2,46 Trii0d0 3 amimyiwrboxybcnzyl Di-N-( 2,4,6-triiodo-3-acetylamino-benzyl)-earbamic carbamic acid B-methoxyethyl ester was aeetylated in acid y gly l ester (Compound A) I80 ml glacial acetic acid with 30 ml acetic anhydride 545 g 3 A i rh l-5 i -2,4,6-1 ii doben i and ().l ml concentrated sulfuric acid by stirring for 4 acid was ded in 80 ml dimethylacctamide, and hours on a steam bath, and the crude Compound No. l0.25 g ethyleneglycol dichloroformate (0.055 mole) 8 obtained thereby was purified by conversion to the was added dropwise with stirring. A clear solution was ammonium salt which was salted out of its concenformed at once and was held at 70C for about 4 hours. trated aqueous solution by means of ammonium chlo- It was then evaporated in a vacuum to one half of its inride in an amount of 29.2 g (70% yield). had a melting H itial volume and stirred into 400 ml water. whereby dipoint of l to lC, and gave an R, value of 0.46. 4 y' y l- Calculated for C|,H| |,,N.,O: 24.44% C. 55.3471 l; eq.wt.687.99 Found: 2413 $5.82 690 Compound No. 8 readily dissolves in boiling water. acid ethylencglycol ester was gradually precipitated in methanol. and ethanol. Its sodium and N- crystalline form. It was dissolved in aqueous ammomethylglucamine salts freely dissolve in cold water. as nium bicarbonate solution. re-precipitated with hydrochloric acid, and further purified by suspension in hot EXAMPLE 1g isopropanol and dilute hydrochloric acid. It melted at The use of propionic anhydride in the second stage 145 C and gave an value of of Example 17 produced the expected N-(2.4,6- triiodw3-propylamino-5-earboxy-benzyl)earbamic 30 5322" 2332 I acid B-methoxyethyl ester in a yield of 73%. After purification by being suspended in boiling ethyl acetate. it A suspension of 20 g of the diester in 80 ml glacial melted at 205 to 210C, and gave an R, value of 0.56. acetic acid was heated with stirring to 95C with 2 ml Calculated for CHHHLINEO: 25.66% C; 54.23% I; eq.wt.702.03 Found: 25.88 54.03 704 The free carboxylic acid is sparingly soluble in water, 40 acetic anhydride. and mixed with 0.1 ml concentrated soluble in ethanol. readily soluble in methanol. sulfuric acid. Stirring was continued for 2 hours at Substitution of glycolic anhydride for the propionic 95C, whereby initially a clear solution was formed, anhydride in the procedure of the preceding paragra h and crystalline Compound A later precipitated. It was produced N-(2.4.o-triiodo-3-hydroxyacetylaminopurified by dissolution in ammonium bicarbonate solu- Scarboxy-benzyl)carbamic acid B-methoxyethyl ester tion and precipitation with hydrochloric acid, and fur- (Compound No. IS) in a yield of9l7r. The Compound her by being suspended in hot isopropanol, and by melted at 206 to 208C and gave an R, value of 49, being filtered off with suction and washed with water.

Calculated l'or CHHHIHNZO7: 23.89% C; 54.08% I; eq.wt.703.99 Found: 23.78 53 .8! 707 The compound is soluble in boiling water and readily The purified product weighed 14.4 g (67.5% yield). de-

dissolves in methanol and ethanol. The sodium and N- 55 composed at 246C, and gave an R, value of 0.39.

methylglucamine salts freely dissolve in cold water.

Calculated for C ,,H ,l.;l\l ,O Found:

Compound A is insoluble in water, methanol. ethanol, and chloroform. Water at 20C dissolves at least an equal weight of the sodium and N-methylglucamine salts.

Calculated for C H J N O Found:

eq.wt.7 1 an:

EXAMPLE 20 Di-N-( 2,4,6-triiodo-3-acetylamino-S-carboxy-benzyl carbamic acid 1,3-propanediol ester (Compound B) 54.3 g 3-Aminomethyl-5-amino-2,4.6-triiodobcnzoic 5 acid and l l.05 g l.3-propanediol dichloroformatc were reacted as in Example l9, and the crude product was dissolved in dilute aqueous sodium hydroxide solution at pH not exceeding 7. Insoluble matter was filtered off,

the filtrate was extracted four times with chloroform m and three times with ethyl acetate. the extracts were discarded, and the aqueous phase was exposed to a vacuum to remove residual solvent. The aqueous liquid was acidified with hydrochloric acid to precipitate di- N-( 2,4,6-triiodo-3-amino-5-carboxy benzyl )-carbamic acid, l,3-propanediol ester which was further suspended in boiling isopropanol, thereafter again dissolved in dilute sodium hydroxide, and precipitated with dilute hydrochloric acid. The purified product was recovered in an amount of 48.2 g (79.5% yield), sintercd at 145C, decomposed at l94C, and gave an R; value of 0.67.

Calculated for C H I NKL: ZL-l-X'u' C; 6| 93% I Found: 2 l .95 61.30

It was further reacted in an amount of 24.6 g with 8 ml acetic anhydride in 96 ml glacial acetic acid in the presence of 0.5 ml concentrated sulfuric acid as described in Example 19, and the crude Compound C so obtained was purified by dissolution in 15% ammonium hydroxide solution, precipitation by dropwise addition of the solution to dilute hydrochloric acid, second dissolution in little ammonium hydroxide solution. and salting out of the ammonium salt from the solution with ammonium chloride. The ammonium salt was dissolved in water, decomposed with dilute hydrochloric acid. and the free acid was again dissolved in sodium hydroxide gradually added to maintain a pH not higher than 7. Impurities were removed by filtration and carbon treatment of the filtrate, and the pure Compound C was ultimately precipitated with hydrochloric acid in an amount of l5.3 g (53% yield). It sintered at 178C, decomposed at 212C, and gave an R, value of 0.46.

Calculated for C. .,H,,.I N O,.: 20.75% C; 62.639? I, Found: 20.80 62.36

Calculated for C H I. m

Found:

cq.wt.656.96 23.43 sans 648 The ester was acetylated as in Example 19, but did not require suspension in isopropanol for purification. Compound B was recovered in a yield of 82.5%. sintered at 190C. decomposed at 2l0C. and gave an R,

value of 0.49.

Compound B dissolves poorly in water and chloroform,

very readily in methanol and ethanol. lts sodium and N-methylglucamine salts dissolve in approximately equal weights of water at 20C.

The acid is only sparingly soluble in water and chloroform, but readily dissolves in methanol and ethanol. The sodium and N-methylglucamine salts dissolve in water at 20C in respective amounts of more than [00 g and approximately g.

EXAMPLE 22 Di-N-( 2,4,6-triiodo- 3-acetylamino-5-carboxy-bcnzyl carbamic acid Lo-hexanediol ester (Compound D) Found:

22.92% C; 60.54% I; eq.wt.628.96 22.6l 60.42 633 EXAMPLE 21 Di-N-( 2,4,6-triiodo-3-acetylamino-5-carboxy-benzyl carbamic acid l,4-butanediol ester (Compound C) 54.5 g 3-Aminomethyl-5-amino-2.4,6-triiodobenzoic acid and l L8 g l.4-hutanediol dichloroformate were It was aeetylated in an amount of 28.8 g in l [2 ml glacial acetic acid with 9.2 ml acetic anhydride in the pres- 5 ence of 0.5 ml sulfuric acid, and Compound D was re covered in an amount of 21 g (68% yield), sintered at 170C, decomposed at 220-225C. and gave an R, value of 0.47.

Calculated for C H h N O Found:

25.06% C; 56.74% I; eq.wt.67(l.9'-) 25.23 56.71 672 reacted as in Examples l9 and 20. The homologous Compound D is insoluble in water and chloroform.

product was recovered in an amount of 28.1 g (45.6?! but easily soluble in methanol and ethanol. More than yield). melted at 235C (decomp). and gave an R,- value of 0.39.

g of the sodium and Nmethylglucamine salts dissolves in water at 20C.

EXAMPLE 23 Di-N-( 2,4,6-triiodo-3-acetyIamino-5-carboxy-benzyl earbamic acid diethyleneglyeol ester (Compound E) A solution of 0.l mole 3-aminomethyl-5-amino- 2,4,6-triiodobenzoic acid in 500 ml water and I ml l-N sodium hydroxide solution was gradually mixed at -I5C with 0.05 mole freshly distilled diethyleneglycol diehloroformate in 50 ml acetone and I00 ml l-N sodium hydroxide solution in such a manner that the pH of the mixture was held between 10 and II. Stirring was then continued for about 1 hour at room temperature, whereupon the mixture was adjusted to pH 7 and extracted with chloroform and ethyl acetate. Residual organic solvent was removed from the aqueous liquid in a vacuum, and the liquid was then acidified to precipitate 62.6 g di-N-(2,4,6-triiodo-3-amino- 5-carboxy-benzyl)-carbamic acid diethyleneglycol ester (99% yield) which sintered at l35C and decomposed at I 91C.

weight calculated for 1.5 H 0 is 636.24, while 635 was w found.

54.3 g 3-Aminomethyl-5-amino-2,4,6-triiodobenzoic acid (0.l mole) was reacted with I3.75 g (0.05 mole) triethyleneglycol dichloroformate as in Example 23 to produce the crude 3-amino analog of Compound F in 5 an amount of 52.25 g (8I7r yield). When triturated with water, the crude material crystallized. it was dissolved in dilute sodium hydroxide solution, and the solution was added dropwise to an excess of dilute hydrochloric acid to precipitate 47 g of a purified intermedi- I() ate sintering at I I2C, decomposing at 133C, and giving an R, value of 0.63.

Found: 22.38 59.30

44 g Di-N-(2,4,6-triiodo-3-amino-5-carboxy-benzyl)- carbamic acid triethyleneglycol ester (0.034 mole) was acetylated in 190 ml glacial acetic acid with 13.6 ml acetic anhydride and 0.7 ml concentrated sulfuric acid. The crude Compound F was dissolved in dilute sodium hydroxide solution, reprecipitated with hydrochloric acid, and further purified by mixing a solution of the acid in ethanol with 5.5 ml cyclohexylamine, permitting the salt to crystallize overnight, and decomposing it in aqueous solution with hydrochloric acid. The pure compound was recovered in a yield of 3l g 657: decomposed at 203C, and gave an R, value of 0.46.

Calculated for C H laM i-i Found 24.48% C; 55.42% I; eq.wt.686.99 24.58 54.55 697 The ester was acetylated as in the preceding Examples with a yield of 47 g (78.5% Compound E sinters at I83C, decomposes at 210C. and gives an R, value of 0.48.

It is only sparingly soluble in water and chloroform, but very soluble in methanol and ethanol. At least I00 g of the sodium and N-methylglucamine salts dissolves 40 in 100 ml water at C.

Calculated for C,,,H L,N,O 23.48% C; 57.25% I; Found: 23.20 57. l0

eq.wt.664.96

(2 mole) in I000 ml ethyl ether. The temperature then was raised stepwise for minutes each to 0, 10, and

EXAMPLE 25 Di-N-( 2,4,6-triiodo-3-hydroxyacetylamino-5-earhoxybenzyl)-carbamic acid ethyleneglycol ester (Compound G) l0 g Di-N-( 2,4,6-triiodo-3-amino-5-carboxy-benzyl carbamic acid ethyleneglycol ester (0.008 mole) was prepared as in Example l9 and dissolved in 60 ml dimethylacetamide. The solvent was partly distilled off to 55 mole) water, and 4.35 g (0.032 mole( acetoxyacetyl chloride was added dropwise at 2-3C. The reaction mixture was stirred 10 hours, and thereafter poured into I50 ml water. The mixture was adjusted to pH I I by adding ml l-N sodium hydroxide solution, kept 20C, and ultimately for 2 hours to 35C. The solvent 60 at C for l hour, filtered, and stirred into ml dilute hydrochloric acid, whereby Compound G was precipitated and could be recovered in an amount of 9 g yield). It melted at 220C (decomp.) and gave an R; value of 0.33.

Found:

21.29% C; 56.23% I; 2.66% H O 2l.l8 55.75 2.72

25 26 The sodium and N-methylglucamine salts are very di-N-(2.4,6-triiodo-3-acctylamino-S-carboxy-bensoluble in water. zyl)-carbamic acid tetraethyleneglycol ester,

di-N-( 2,4.6-triiodo-3-hydroxyacetylamino-5- EXAMPLE 26 carboxy-benzyl)-earbamic acid tetraethyleneglycol Di-N-( 2,4,6-triiodo-3 -methoxyacetylamino-S-carboxy- 5 ester,

benzyl)-carbamic acid ethyleneglycol ester 4 yzyl)-carbamic acid pentaethyleneglycol ester. and di-N-( 2,4,6-triiodo-3-hydroxyacetylamino-5- carboxy-benzyl)-carbamic acid pentaethylenegl2 g Di-N-( 2,4,6-triiodo-3-amino-S-carboxy-benzyl carbarnic acid ethyleneglycol ester was reacted with 2.7 g methoxyacetyl chloride in a manner otherwise l0 analogous to the procedcure of Example 25. The delyco ester sired compound was obtained in an amount of l3.l g EXAMPLE 23 977. ield decom osed at l90C, and ave an R f 0 p g I Solutions for intravenous administration prior to e urography were prepared to the following typical compositions:

Calculated for C H l Np 23.20% C; 56.57% I Found: 22.94 56.85 Compound No. R g 542.5

Compound No. 4. g (v02 N-Mcthylglucamine. g I344 9 .6 I 2() Sodium hydroxide g 4.0 The sodium and N-methylglucamme salts readily dlS- Monoethanolamine, g 23.7 golve in water Disodium EDTA (ll 0.] Bidistilled water to make ml I000 I000 lodin m ml 300 340 EXAMPLE 2? 246'triiodo'? hyqmxyaccty|amino'5'Carboxy' 25 Disodium EDTA was dissolved first in a small portion benZyU-cmbam'c dlethylencglycol ester of the water, and the radiopaque material, the N- l2.45 g Di-N-(2,4,6-triiodo-3-amino-5-carboxy-benmethylglucamine, and the other base were added sc- ZyU-carhamic acid diethylaneglycol ester prepared as quentially with stirring. The concentrated solution was in Example 23 was reacted with 6.8 g acetoxyacetyl adjusted to pH 7.11:0.2 and diluted to I000 ml. The dichloride in the manner of Example 25. The desired luted solution was filtered and distributed in glass vials compound was obtained in an amount of l 1.6 g (85.37: in batches of IO, 20, and 30 ml. The vials were sealed yield), melted at 21 32l4C, and gave an R, value of and sterilized for about 15 minutes at l 10C.

0.27. Other solutions for intravenous administration prior Calculated for C H, ,I,,N O, 22.93% C; 55.90% I; eq.wt.68l

Found: 2254 55.22 675 The sodium and N-methylglucamine salts dissolve very to urography prepared in an analogous manner from easily in water. 40 other monoesters of the invention had an iodine con- The following additional compounds were prepared t nt f mg/m t 00 g/ml.

in the rhanner evident from Examples 1 to 27:

N-( 2.4,6-triiodo-3-a-hydroxy-propionylamino-5- EXAMPLE 29 carboxy-benzyl)-carbamic acid methyl ester, Solutions for administration prior to and during vadi-N-(2,4,6-triiodo-3-propionylamino-S-carboxy- 45 sography were prepared in the manner of Example 28 benzyl)earbamic acid diethyleneglycol ester, t0 the l Wing ypical Compo i ions:

Compound No. 3 g 6935 Compound No. l3. g 555 Compound G, g 890 N-Methylglucamine. g 78.1 85.5 Methylxylamine. g 47.7 Sodium hydroxide, g 24 l0 l7.54 Tris-( hyd roxymethyl )-aminomethane,g 6.3 lMethylamino-2,3-propanediol, g 26.3 46.1 Disodium EDTA g (H 0.1 0.2 Bidistillcd water. to make ml l000 I000 I250 iodine mg/ml 400 300 400 di-N-Z,4,6-triiodo-3-methoxyacetylamino-S-car- The cations present in solutions for vasography may be boxy-benzyl carbamic acid diethyleneglycol esvaried widely to suit specific requirements of angiocarter, diography, cerebral angiography, aortography, phledi-N-( 2.4,6-triiodo-3-a-hydroxypropionylamino-S- beography, lymphography, hystero-salpingiography, carboxy-benzyl )-carbamic acid diethyleneglycol splenoportography, etc., and the iodine content may be ester. adjusted correspondingly to lSO-SOO mg/ml. Basically di-N-(2.4.o-triiodo-3-hydroxyacetylamino-5- similar solutions, when administered by infusion, may

carboxy-benzyl)-carbamic acid triethyleneglycol contain 45 to I50 mg iodine per milliliter. ester,

di-N-( 2,4,6-triiodo3-oz-hydroxypropionylamino-5- EXAMPLE 30 carboxy-benzyl)-carbamic acid triethyleneglycol The solutions listed below have been used successester. fully in cholecystography and cholangiography:

Compound E. g 524.3 (ompound C. g 259 Compound F. g 27l Compound 8. g 85.4 N-Mcthylglucamine. g l 15 57.4 25.7 N-Methylxylaminc. g 32.] Sodium hydroxide 8.0 4.0 8.0 Disodiuni EDTA. g (Ll 0.] 0.1 0.05 Bidistilled water to make ml I000 I000 I000 I000 Iodine. mg/ml 300 I50 I50 5( Solutions containing l50 to 400 mg iodine per milliliter 3-methylureidomethyl-5-acetylamino-bcnzoic acid N- are preferred for intravenous administration, and an methylglucamine salt. 2% hydrolysis was noted after 30 iodine concentration of 45 to 150 mg/ml is generally minutes, and l7l after lSO minutes. chosen for application by infusion. TABLE EXAMPLLE 31 IS Compound Toxicity Excretion '71. with To test the thermal stability of the compounds of this Nu LDM mg "kg Urine invention. aqueous solutions of the N-methylglucamine salts of the carhamic acid ester derivatives prepared in g g :2 Examples 6. [0, l l. and lb were subjected to a temper- 2U 3 77m 5 ature of 120C in sealed containers for 30 minutes and g Z :2 for ISO minutes. and the contents of each container were thereafter analyzed for hydrolysis of the CO-NH 7 6900 l l 74 bond in the carhamate group. S m

No measurable hydrolysis was found in the ethyl car- 25 m 6800 71 hamate group of the compound of Example 6 nor in the 1 7050 33 isopropyl carbamatc group of the compound of Exam- L 6300 ple 10 even after ISO minutes. 0.57: Hydrolysis was found after 30 minutes heating in the 62-hydroxyethyl TABLE II carhamate group of Example I l. and V7: after 150 min- 30 utcs at lC. The compound of Example 16 showed 0.7% hydrolysis in the 2.3-dihydroxypropyl carhamate Cmnvmnd Tvxicit) Emrelifin i h N l r group after minutes and not more than l.8/( after 0 LDm'mL Elle Urme 150 minutes. A 8:00 56 I) By way ofcomparison. 10% hydrolysis within 30 ming 22 utcs was found in the NHCO-CH CH OH side D 5 78 chain of 2.4,6-triiodo-3-acetylaminomethyl-5-'yl IU5W 60 3 x I 10200 60 I9 hydroxyproptonylamlno bLJlZOIC acid N G 1227 76 I 3 methylglucamme salt, and the same side chain was H 2400 3s 33 about 30% hydrolyzed after 150 minutes. The H N- 40 a" CO-NHCh side chain in 2.4,6-triiodo-3- 7 TABLE lll Compd Ani- Cholecystography. after C holangiography. after No. mal 0.5 l 2 4 8 hrs 0. l 2 4 hrs A l l l l l 2 I5 I l 0 0 2 0 0.5 0.5 2 2.5 2 0.5 l.5 l B l 2 2 3.3 3 3 2.5 3 3 4 2 l 1.5 2.5 2.24 2.8 2.8 3.3 3.3 2.5 C 1 L8 2 2.3 3 2.5 2.5 3 3.3 l l 2 1.3 2.3 2.3 3 2.5 2.5 2.8 2.5 2 D l 0.8 L5 2 2 L8 1.8 2.3 l 0.5 O 2 l 2.3 2.5 2.5 2.5 2.5 2.5 2.5 2.3 0 E l [.5 2.3 2.5 2.5 2.5 2.5 3 2.8

2 l Ls 2.1 2.8 2.5 2.5 3 3 3 2 F 2 0.5 1.5 2.5 2.5 2.8 2.5 l 2.8 4 4 G 2 0.25 l 2 2.5 2s 2.8 l L5 L5 H l 0.9 L4 L8 2.3 2 2.3 L8 0.5 0.9 l l 0.8 L3 L7 1.8 1.) 1.5 0.75 0.5 0.3

ureidomethyl-5-acetylamino-benzoic acid N- What is claimed is: methylglucamine salt was split 3 5 7r after 30 minutes I. A compound which is an N-(2,4,6triiodo-3- of heating. and l2-IS'7: after 120 minutes. In the hoacylamino-S-carboxy-benzyl)-carbamic acid ester of mologous methylurcidomethyl group of 2,4,6-triiodo' the formula or a water-soluble salt of said ester with a pharmaceutically acceptable base, in said formula n being l or 2,

R, having up to four carbon atoms and being alkyl,

hydroxyalkyl, or alkoxyalkyl when n is l, and said R, being divalent alkylcne or oxaalkylene having one to five carbon atoms and up to two oxygen atoms when n is 2, and

R having up to three carbon atoms and being alkyl,

hydroxyalkyl, or alkoxyalkyl.

2. A compound as set forth in claim 1 which is a salt of said ester with a base selected from the group consisting of the hydroxides of sodium, lithium, calcium, and magnesium. and organic amines;

3. A compound as set forth in claim I, wherein n is l.

4. A compound as set forth in claim 3, wherein R, is methyl, ethyl, 62-hydroxyethyl, l,3-dihydroxyisopropyl, l,3-dihydr0xypropyl. 62-hydroxyethyl, or 62- methoxy-ethyl; and R is methyl, ethyl, hydroxymethyl, or methoxymethyl when R, is methyl or ethyl, said R being methyl or ethyl when R, is B-hydroxyethyl; said R being methyl when said R, is dihydroxyisopropyl or dihydroxypropyl; and said R being methyl, hydroxymethyl, or methoxymethyl when said R, is B-methoxymethyl.

5. A compound as set forth in claim 1, wherein n is 2, and R, is divalent, straight-chained alkylene having up to three carbon atoms.

6. A compound as set forth in claim 5, wherein R is methyl.

7. A compound as set forth in claim I, wherein n is 2, and R, is a divalent radical of the formula -CH- CH (OCH CH wherein m is l or 2.

8. A compound as set forth in claim 7, wherein R is methyl, ethyl, hydroxymethyl, or methoxymethyl.

9. A compound as set forth in claim 1, wherein said base is an alkanolamine.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,910,989 DATED I October 7 1975 INV ENTOR(S) I Ernst Felder et a].

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In claim 1 (column 29) change the formula to read R -CO'-NH CH2-NH-CQ-ORl n Signed and Scaled this thirtieth Day of 0mm 1975 [SEAL] Arrest:

RUTH C. MASON Commission" of hulls ind Trademark: 

1. A COMPOUND WHICH IS AN N-(2,4,6-TRIIODO-3-ACYLAMINO-5CARBOXY-BENZYL)-CARBAMIC ACID ESTER OF THE FORMULA FFIG-01 OR A WATER-SOLUBLE SALT OF SAID ESTER WITH A PHARMACEUTICALLY ACCEPTABLE BASE, IN SAID FORMULA N BEING 1 OR 2, R1 HAVING UP TO FOUR CARBON ATOMS AND BEING ALKYL, HYDROXYALKYL, OR ALKOXYALKYL WHEN N IS 1, AND SAID R1 BEING DIVALENT ALKYLENE OR OXAALKYLENE HAVING ONE TO FIVE CARBON ATOMS AND UP TO TWO OXYGEN ATOMS WHEN N IS 2, AND R2 HAVING UP TO THREE CARBON ATOMS AND BEING ALKYL, HYDROXYALKYL, OR ALKOXYALKYL.
 2. A compound as set forth in claim 1 which is a salt of said ester with a base selected from the group consisting of the hydroxides of sodium, lithium, calcium, and magnesium, and organic amines.
 3. A compound as set forth in claim 1, wherein n is
 1. 4. A compound as set forth in claim 3, wherein R1 is methyl, ethyl, 62-hydroxyethyl, 1,3-dihydroxyisopropyl, 1,3-diHydroxypropyl, 62-hydroxyethyl, or 62-methoxy-ethyl; and R2 is methyl, ethyl, hydroxymethyl, or methoxymethyl when R1 is methyl or ethyl, said R2 being methyl or ethyl when R1 is -hydroxyethyl; said R2 being methyl when said R1 is dihydroxyisopropyl or dihydroxypropyl; and said R2 being methyl, hydroxymethyl, or methoxymethyl when said R1 is Beta -methoxymethyl.
 5. A compound as set forth in claim 1, wherein n is 2, and R1 is divalent, straight-chained alkylene having up to three carbon atoms.
 6. A compound as set forth in claim 5, wherein R2 is methyl.
 7. A compound as set forth in claim 1, wherein n is 2, and R1 is a divalent radical of the formula -CH2-CH2-(O-CH2-CH2)m - wherein m is 1 or
 2. 8. A compound as set forth in claim 7, wherein R2 is methyl, ethyl, hydroxymethyl, or methoxymethyl.
 9. A compound as set forth in claim 1, wherein said base is an alkanolamine. 